Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium-regulated protein phosphatase calcineurin (PP2B) functions as a regulator of gene expression in diverse tissues through the dephosphorylation and activation of a family of transcription factors known as nuclear factor of activated T cells (NFAT). Here we show that NFATc3, in addition to being calcium responsive, is regulated through an indirect recruitment of class II histone deacetylases (HDACs). Specifically, yeast two-hybrid screening with the rel homology domain of NFATc3 identified the chaperone mammalian relative of DnaJ (Mrj) as a specific interacting factor. Mrj and NFATc3 were shown to directly associate with one another in mammalian cells and in vitro. Mrj served as a potent inhibitor of NFAT transcriptional activity within the nucleus through a mechanism involving histone deacetylase recruitment in conjunction with heat shock stimulation. Indeed, Mrj was determined to interact with class II histone deacetylases, each of which translocated to the nucleus following heat shock stimulation. Mrj also decreased NFATc3 occupancy of the tumor necrosis factor-alpha promoter in cardiomyocytes in an HDAC-dependent manner, and Mrj blocked calcineurin-induced cardiomyocyte hypertrophic growth. Conversely, small-interfering-RNA-mediated reduction of Mrj augmented NFAT transcriptional activity and spontaneously induced cardiac myocyte growth. Collectively, our results define a novel response pathway whereby NFATc3 is negatively regulated by class II histone deacetylases through the DnaJ (heat shock protein-40) superfamily member Mrj.
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PMID:The DnaJ-related factor Mrj interacts with nuclear factor of activated T cells c3 and mediates transcriptional repression through class II histone deacetylase recruitment. 1626 Jun 8

The search for effective chemopreventive compounds is a major challenge facing research into preventing the progression of cancer cells. The naturally occurring polyphenol antioxidants look very promising, but their mechanism of action still remains poorly understood. Here, we show that 2-(3,4-dihydroxyphenyl)ethanol (DPE), a phenol antioxidant derived from olive oil, induces growth arrest and apoptosis in human colon carcinoma HT-29 cells. The mechanisms involve prolonged stress of the endoplasmic reticulum (ER) leading to the activation of the two main branches of the unfolded protein response (UPR), including the Ire1/XBP-1/GRP78/Bip and PERK/eIF2alpha arms. DPE treatment led to overexpression of the pro-apoptotic factor CHOP/GADD153 and persistent activation of the Jun-NH2-terminal kinase/activator protein-1 signaling pathway. DPE concomitantly modulated the extracellular signal-regulated kinase 1/2 and Akt/PKB pro-survival factors by altering their phosphorylation status as well as inhibiting tumor necrosis factor-alpha-induced nuclear factor-kappaB activation by inactivating the phosphorylation of nuclear factor inhibitor-kappaB kinase. These findings prompted us to investigate the possible involvement of phosphatases in DPE-mediated action. Using phosphatase inhibitors and RNA interference to silence the Ser/Thr phosphatase 2A (PP2A) prevented DPE-induced cell death. These findings demonstrate that DPE specifically activates PP2A, which plays a key initiating role in various pathways that lead to apoptosis in colon cancer cells.
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PMID:Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. 1652 88

Activation and dysfunction of the endothelium underlie many vascular disorders including atherosclerosis, tumor growth, and inflammation. We recently reported that thrombin and vascular endothelial growth factor, but not tumor necrosis factor-alpha, results in dramatic up-regulation of Down syndrome critical region (DSCR)-1 gene in endothelial cells, a negative feedback regulator of calcineurin-NFAT signaling. Constitutive expression of DSCR-1 in activated endothelial cells markedly impaired NFAT nuclear localization, proliferation, tube formation, and tumor growth. The goal of the present study was to elucidate the relative roles of NFAT/DSCR-1 and NF-kappaB/I-kappaB in mediating thrombin-responsive gene expression in endothelial cells. DNA microarrays of thrombin-treated human umbilical vein endothelial cells overexpressing DSCR-1 or constitutive active IkappaBalpha revealed genes that were dependent on NFAT and/or NF-kappaB activity. Vascular cell adhesion molecule-1 was inhibited both by DSCR-1 and I-kappaB at the level of mRNA, protein, promoter activity, and function (monocyte adhesion). Using a combination of transient transfections, electrophoretic mobility shift assays, and chromatin immunoprecipitation, thrombin was shown to induce time-dependent coordinate binding of RelA and NFATc to a tandem NF-kappaB element in the upstream promoter region of vascular cell adhesion molecule-1. Together, these findings suggest that thrombin-mediated activation of endothelial cells involves an interplay between NFAT and NF-kappaB signaling pathways and their negative feedback inhibitors, DSCR-1 and I-kappaB, respectively. As natural brakes in the inflammatory process, DSCR-1 and I-kappaB may lend themselves to therapeutic manipulation in vasculopathic disease states.
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PMID:Thrombin-induced autoinhibitory factor, Down syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in the endothelium. 1662 81

Using a polyclonal antibody raised against a highly conserved sequence of 38 amino acids containing the activation site (VTDSAAGAT) common to mammalian and yeast alkaline phosphatases (AP), we identified in decapsidated Saccharomyces boulardii a protein phosphatase detected by autoradiography as a single signal (63 kD). Using an affinity chromatography column, the protein phosphatase could be concentrated 39.1-fold and presented as a doublet of two subunits. Compared with rat and bovine purified intestinal AP, the enzyme from S. boulardii had a greater ability to dephosphorylate the lipopolysaccharide (LPS) of Escherichia coli 055B5. When tested in vivo, intraperitoneal injection of intact LPS to rats produced, after 9 h, 100 ng/mL of circulating tumor necrosis factor-alpha with inflammatory lesions and apoptotic bodies in the liver and the heart, whereas rats injected with partially dephosphorylated LPS produced only 40 ng/mL tumor necrosis factor-alpha without organic lesions. In conclusion, S. boulardii is able to inhibit toxicity of E. coli surface endotoxins by the release of a protein phosphatase exhibiting a great capacity of dephosphorylation.
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PMID:Saccharomyces boulardii produces in rat small intestine a novel protein phosphatase that inhibits Escherichia coli endotoxin by dephosphorylation. 1669 Sep 53

NFAT family is recognized as a transcription factor for inflammation regulation by inducing the expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), the key mediator of inflammation, which was reported to induce cell transformation in mouse epidermal Cl41 cells. In this study, we demonstrated that TNF-alpha was able to induce NFAT activation, as well as the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). The induction of COX-2 by TNF-alpha was abolished by knockdown of NFAT3 with its siRNA, while the induction of iNOS was not effected. Moreover, TNF-alpha-induced anchorage-independent cell growth was significantly inhibited by NFAT3 siRNA and cyclosporine A, a chemical inhibitor for the calcineurin/NFAT pathway, which suggests the importance of NFAT3 in regulating TNF-alpha-induced anchorage-independent cell growth. Consequently, impairment of COX-2 by its siRNA or selective inhibitor also inhibited TNF-alpha-induced anchorage-independent cell growth. Taken together, our results indicate that NFAT3 plays an important role in the regulation of TNF-alpha-induced anchorage-independent cell growth, at least partially, by inducing COX-2 expression in Cl41 cells. These findings suggest that NFAT3/cyclooxygenase-2 act as a link between inflammation and carcinogenesis by being involved in the tumor promotion stage.
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PMID:NFAT3 is specifically required for TNF-alpha-induced cyclooxygenase-2 (COX-2) expression and transformation of Cl41 cells. 1680 72

Hypomagnesemia, which is frequently observed in patients treated with calcineurin inhibitors to prevent rejection after allogeneic transplantation, has been associated with a faster rate of decline in allograft function. The effect of hypomagnesemia on lung allograft has not been reported yet. In our model of isolated mouse lung, we have evaluated the early effects of allogeneic lung perfusion with blood from magnesium (Mg)-deficient mice for 3 h on lung activation and remodelling, compared to isogeneic perfusion. Hypomagnesemia (0.21+/-0.07 mmol Mg(2+)/l) was observed in blood from Mg-deficient mice, but no inflammatory pattern. The mRNA level of the intercellular adhesion molecule (ICAM)-1, but neither of the vascular cell adhesion molecule (VCAM)-1, nor of the cytokines tumor necrosis factor (TNF)alpha and interleukin (IL)-2, was enhanced (p<0.05). Although caspase-3 mRNA was transiently enhanced, no apoptotic cells were evidenced in lung tissues even after 3 h. Using cDNA array, we found that the genes encoding RANKL, RANK, TNFR2, NFATX, IL-1R2, IL-6R gp130, SOCS3, PDGFRB, P63, CSF3R, CXCL1, CXCL5, CX3CL1, CSF1, which are involved in inflammation and apoptosis regulation, were markedly up-regulated in allogeneic conditions. Our results support a limited allogeneic activation and an early stage of the inflammatory process in lung, at the time of inflammatory cell recruitment without lung tissue remodelling, as a result of hypomagnesemia. These findings suggest that cyclosporine-related hypomagnesemia, observed in most of the transplanted patients, does not constitute an additional risk for lung allograft outcome.
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PMID:Allogeneic activation is attenuated in a model of mouse lung perfused with magnesium-deficient blood. 1713 54

The switching on-and-off of I-kappaB kinase (IKK) and NF-kappaB occurs rapidly after signaling. How activated IKK becomes down-regulated is not well understood. Here we show that following tumor necrosis factor-alpha stimulation, protein phosphatase 2A (PP2A) association with IKK is increased. A heptad repeat in IKKgamma, helix 2 (HLX2), mediates PP2A recruitment. Two other heptad repeats downstream of HLX2, termed coiled-coil region 2 (CCR2) and leucine zipper (LZ), bind HLX2 and negatively regulate HLX2 interaction with PP2A. HTLV-1 transactivator Tax also binds HLX2, and this interaction is enhanced by CCR2 but reduced by LZ. In the presence of Tax, PP2A-IKKgamma binding is greatly strengthened. Interestingly, peptides spanning CCR2 and/or LZ disrupt IKKgamma-Tax and IKKgamma-PP2A interactions and potently inhibit NF-kappaB activation by Tax and tumor necrosis factor-alpha. We propose that when IKK is resting, HLX2, CCR2, and LZ form a helical bundle in which HLX2 is sequestered. The HLX2-CCR2-LZ bundle becomes unfolded by signal-induced modifications of IKKgamma or after Tax binding. In this conformation, IKK becomes activated. IKKgamma then recruits PP2A via the exposed HLX2 domain for rapid down-regulation of IKK. Tax-PP2A interaction, however, renders PP2A inactive, thus maintaining Tax-PP2A-IKK in an active state. Finally, CCR2 and LZ possibly inhibit IKK activation by stabilizing the HLX2-CCR2-LZ bundle.
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PMID:Heptad repeats regulate protein phosphatase 2a recruitment to I-kappaB kinase gamma/NF-kappaB essential modulator and are targeted by human T-lymphotropic virus type 1 tax. 1731 97

We have previously shown that procaspase-3 exists in a high molecular weight complex in neonatal rat brain. Here, we purify and identify the protein that interacts with procaspase-3 from rat neonatal cortex. We searched binding proteins to procaspase-3 from a cytosolic extract of neonatal rat brain using chromatogram, two-dimensional gel electrophoresis, and far Western immunoblot. Analysis by tandem mass spectrometry identified the protein as a regulatory subunit of calcineurin (calcineurin B). Overexpression of calcineurin B in HEK293 cells potentiated processing of caspase-3 and apoptosis triggered by tumor necrosis factor-alpha and cycloheximide treatment. In a cell-free system, overexpression of calcineurin B in HEK293 cells markedly increased processing of caspase-3 by cytochrome c. Immunodepletion of calcineurin B from cytosolic extracts from Jurkat cells decreased processing of caspase-3 by cytochrome c. Knockdown of calcineurin B by RNA interference resulted in reduced apoptosis in HEK293 cells but not in caspase-3-deficient MCF-7 cells. These results suggest that calcineurin B potentiates the activation of procaspase-3 by accelerating its proteolytic maturation.
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PMID:Calcineurin potentiates the activation of procaspase-3 by accelerating its proteolytic maturation. 1732 36

Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor kappaB (NFkappaB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti-inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFkappaB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-alpha or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression.
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PMID:Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals. 1769 57

Wear particles produced from artificial joint prostheses are known to cause macrophage-monocyte lineage cells to produce proosteoclastogenic cytokines, including tumor necrosis factor (TNF)-alpha. The specific molecular mechanism, however, is not yet known. Bioinformatic analysis showed that the promoter region of TNF-alpha has several consensus sequences for NFAT binding. Consequently, we examined the role of nuclear factor of activated T cells (NFAT) in TNF-alpha production. Our investigation has shown that treatment with titanium nanoparticles increased TNF-alpha gene expression along with TNF-alpha protein secretion in murine macrophage-like RAW264.7 and primary monocyte-macrophage cells. Titanium particle-induced TNF-alpha induction was inhibited by VIVIT, a peptide inhibitor that targets the calcineurin/NFAT axis, which suggests that NFAT mediates metallic particle-induced TNF-alpha expression in monocyte-macrophage lineage cells.
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PMID:Orthopedic implant particle-induced tumor necrosis factor-alpha production in macrophage-monocyte lineage cells is mediated by nuclear factor of activated T cells. 1805 40


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